Antiandrogenic 17-alpha-alkyl steroids

ABSTRACT

17 alpha -substituted steroids of the formula   &lt;IMAGE&gt;   wherein R1 is hydrogen, acyl, alkyl, alkenyl, alkyl or alkenyl interrupted by an oxygen atom, cyclopentyl, or tetrahydropyranyl, R2 is alkyl or alkenyl of 2-6 carbon atoms, X is oxygen or the grouping H(OR3) wherein R3 is hydrogen, acyl, alkyl, alkenyl, alkyl or alkenyl interrupted by an oxygen atom, cyclopentyl, or tetrahydropyranyl, upon topical application, display antiandrogenic properties and can be utilized for the treatment of acne, seborrhea, alopecia and hirsutism.

This is a continuation, of application Ser. No. 784,121, filed 10/04/85,now abandoned, which is is a div. of Ser. No. 620,216, filed 06/13/84,now U.S. Pat. No. 4,558,041, which is a div. of Ser. No. 380,328, filed05/20/82, now U.S. Pat. No. 4,456,600, which is a div. of Ser. No.198,383, filed 10/20/80, now U.S. Pat. No. 4,344,941.

BACKGROUND OF THE INVENTION

The present invention relates to new antiandrogenic steroids.

The compound of formula I below wherein R₁ and R₂ are hydrogen and X isoxygen, known as "mesterolone" is a strongly orally effective androgen.Mesterolone (1-αmethylandrostan- 17β-ol-3-one) is described, forexample, in German Patent No. 1,152,100 and in "Arzneimittel-Forsch."[Drug Research] 16, 4 : 455-466 (1966).

SUMMARY OF THE INVENTION

It is an object of this invention to provide new steroids havingvaluable pharmacological properties.

Upon further study of the specification and appended claims, furtherobjects and advantages of this invention will become apparent to thoseskilled in the art.

These objects have been attained in one aspect of this invention byproviding 17α-substituted steroids of formula (I) ##STR2## wherein R₁ ishydrogen, acyl, alkyl, alkenyl, alkyl or alkenyl interrupted by anoxygen atom, cyclopentyl or tetrahydropyranyl,

R₂ is alkyl or alkenyl of 2-6 carbon atoms,

X is oxygen or the grouping H(OR₃) wherein R₃ is hydrogen, acyl, alkyl,alkenyl, alkyl or alkenyl interrupted by an oxygen atom, cyclopentyl ortetrahydropyranyl.

DETAILED DISCUSSION

The steroids of this invention contain an alkyl or alkenyl group R₂ inthe 17α-position. Such groups include those of 2-6 carbon atoms,preferably those which are straight chained. Suitable groups R₂ include,for example, ethyl, propyl, butyl, pentyl and hexyl, propenyl etc.Branched groups include those such as isobutyl and isobutenyl.

The steroids of formula I contain a free, esterified or etherifiedhydroxy group (OR₁ or OR₃) in the 17α- and optionally also in the 3α- or3α-position.

The esters OR₁ and OR₃ are derived from the acids customary in steroidchemistry. (See, e.g., U.S. Pat. No. 4,011,314). whose disclosure isincorporated by reference herein). Examples include organic carboxylicand sulfonic acids of 1-17 carbon atoms generally of a hydrocarbonnature, or equivalently, a substituted hydrocarbon nature; preferablyutilized are organic carboxylic acids of 1-7 carbon atoms. Examples ofsuitable acyl groups R₁ and R₃ include formyl, acetyl, propionyl,butyryl, isobutyryl, caproyl, heptanoyl, chloroacetyl, trifluoroacetyl,glycoloyl, succinyl, glutaryl, adipoyl, dimethylaminopropionyl, benzoyl,nicotinoyl, isonicotinoyl, etc.

The ethers OR₁ and OR₃ contain an alkyl, alkenyl, cyclopentyl ortetrahydropyranyl group. Alkyl or alkenyl groups R₁ and R₃ preferablycontain 1-5 carbon atoms and optionally are interrupted by an oxygenatom. Examples of such R₁ and R₃ groups include methyl, ethyl,methoxymethyl, methoxyethyl, ethoxyethyl, propyl, butyl, pentyl, etc.

The steroids of formula I can be prepared by reacting a 17-keto steroidof formula II ##STR3## wherein Y is an acid-hydrolyzable, blocked 3-oxogroup, with an R₂ organometallic compound to form the corresponding17α-R₂ steroid; splitting off the blocking group in the 3-position; and,depending on the particularly desired form of R₁ and X in the finalproduct, optionally esterifying or etherifying the 17-hydroxy groupprior to or after the blocking group splitting-off step; and/or reducingthe 3-keto group and/or, optionally, subsequently esterifying oretherifying free hydroxy groups in the 3-position or in the 3- and17-positions.

This process is conducted using fully conventional reactions andprocedures. For reacting the 17-keto group with an organometal compoundyielding the residue R₂, the keto group must be blocked in the3-position. The blocking group Y is to be cleavable by acidichydrolysis. In a preferred embodiment, the keto group in the 3-positionis blocked by ketal formation. The ketal residues Y are derived from thealcohols and thioalcohols usually employed for protecting free oxogroups. Examples include: ethylene glycol, 2,2-dimethyl-1,3-propanediol,and 1,2-ethanedithiol, etc. However, the 3-keto group can also beprotected by enolether, enol ester, or enamine formation.

The reaction of the 17-keto compound of formula II can be conductedusing with an organometallic compound (R₂ -metal), especially with R₂-lithium, e.g. n-butyllithium, using conventional methods. Theorganometallic compound can also be produced in the reaction solutionfrom the haloalkane and the alkali metal, such as, for example,1-bromopentane or 1-bromohexane and lithium. The reaction is conductedin an inert solvent, e.g. ether, tetrahydrofuran, hexane, etc. Thereaction temperature is 0° to 50° C., preferably room temperature.

To produce the 17α-propyl compound (R₂ =propyl), the 17α-allyl compoundis preferably formed-first of all by Grignardization with allylmagnesiumbromide, and this compound is subsequently hydrogenated to the17α-propyl compound. Hydrogenation takes place with catalyticallyactivated hydrogen. Examples of suitable catalysts include palladium oncarbon in methanol or tris(triphenyl) phosphine rhodium chloride inacetone. Analogously, the 17α-isobutyl compound is prepared by way ofthe 17α-isobutenyl compound.

The 17α-ethyl compound (R₂ =ethyl) can be produced, for example, also ina manner known per se by way of the 17α-ethynyl compound. For thispurpose, the 17-keto compound of formula II is converted, for examplewith ethynylmagnesium bromide or lithium acetylide, into the 17α-ethynylcompound, and the latter is then hydrogenated to the 17α-ethyl compound.

The 3-keto blocking group (Y) is split off, either before or optionallyalso after the possible esterification or etherification of the17-hydroxy group, in accordance with methods known to those skilled inthe art by means of acidic hydrolysis. To split off the blocking groups,suitable agents include mineral acids, e.g. perchloric acid, sulfuricacid, hydrochloric acid, or organic acids, such as, for example, oxalicacid. The splitting step is preferably effected in an alcoholic solutionor in other polar solvents, e.g. acetone, at temperatures of about 20°to 100° C.

The processes customarily utilized in steroid chemistry for theesterification of tertiary steroid alcohols can serve for the optionallyfollowing esterification of the tertiary 17-hydroxy group, e.g. reactionwith acids or acid anhydrides in the presence of strong acids, e.g.trifluoroacetic acid or p-toluenesulfonic acid, at temperatures of about10° to 50° C., or the reaction with an acid anhydride in the presence ofa tertiary amine, e.g. pyridine or collidine, at about 20° to 200° C. Ifpyridine and 4-(dimethylamino) pyridine are used together as thetertiary amines, the esterification of the teriary 17-hydroxy group canalso be conducted at room temperature.

Alkylating compounds, such as, for example, alkyl halogenides, can beused for the etherification of the 17-hydroxy group or the hydroxygroups in the 3- or in the 3-and 17-positions. The etherification takesplace conventionally in the presence of a strong base, such as sodiumhydroxide solution, using a polar solvent, such as hexamethylphosphorictriamide, at 0°-50° C. or in the presence of a strong base, such assodium hydride, with the use of an ether, such as tetrahydrofuran, at30°-100° C.

For the preparation of alkyl ethers, the carbon chain of which isinterrupted by an oxygen atom and optionally closed to a ring, thehydroxy compounds are converted with dihydropyran or alkyl vinyl ethersin the presence of a strong acid, such as p-toluenesulfonic acid orphosphorus oxychloride, into the corresponding tetrahydropyranyl oralkoxyethyl ethers. The reaction is preferably carried out in thepresence of inert solvents, such as chloroform, dichloromethane,tetrahydrofuran, dioxane, etc., at a reaction temperature of -20° to100° C. For the production of methoxymethyl ethers, the hydroxy compoundis reacted, for example, with formaldehyde dimethylacetal in anhydrousdichloromethane in the presence of phosphorus pentoxide at roomtemperature.

The reduction of the keto group in the 3-position can be conductedaccording to known methods by hydrogenation with a metal hydride.Especially suitable hydrogen donors proved to be complex hydrides, e.g.sodium borohydride and lithium tri-(tert-butoxy) aluminum hydride. Thereduction of sodium borohydride is preferably accomplished in anaqueousalcoholic solution, and the reduction with lithiumtri-(tert-butoxy)-aluminum hydride is carried out in an ether solution.The reduction is effected under gentle conditions, preferably attemperatures of about 0° to 50° C.

An example for the subsequent esterification of the hydroxy group in the3-position is the reaction with an acid anhydride or halogenide in thepresence of a tertiary amine, such as, for example, pyridine, collidine,or triethylamine, at room temperature. The 3-hydroxy group can also beesterified with the acid anhydride with the use of a strong acid, suchas p-toluenesulfonic acid, or with the corresponding acid andtrifluoroacetic anhydride at room temperature.

When conducting the esterification in the presence of an acidic catalystat room temperature or in the presence of an alkaline catalyst at anelevated temperature of 20°-200° C., the hydroxy groups in the 3- and17-position can also be esterified simultaneously.

If pyridine and 4-(dimethylamino) pyridine are used together as thealkaline catalysts, then both hydroxy groups can also be esterified inan alkaline medium at room temperature.

The starting material 17-keto steroids of formula II can be producedaccording to methods known per se from1α-methyl-5α-androstan-17β-ol-3-one by the introduction of a blockinggroup in the 3-position and oxidation in the 17-position. Thepreparation of compounds of formula II is explained below in greaterdetail, using as an example the production of3,3-ethylenedioxy-1α-methyl-5α-androstan-17-one:

20 g of 17β-hydroxy-1α-methyl-5α-androstan-3-one is stirred under refluxwith the use of a water trap in 500 ml of benzene with 60 ml of ethyleneglycol and 600 mg of p-toluenesulfonic acid for 5.5 hours. Aftercooling, the reaction solution is diluted with ether, washed with sodiumbicarbonate solution and water, and dried. Yield after evaporation: 23 gof crude 3,3-ethylenedioxy-1α-methyl-5α-androstan-17β-ol.

23 g of 3,3-ethylenedioxy-1α-methyl-5α-androstan-17β-ol is agitated for1 hour at room temperature in 230 ml of dichloromethane with 20 g ofpyridinium chlorochromate in the presence of 20 g of sodium acetate. Thereaction solution is then diluted with ether, filtered off from theinsoluble proportions, and the filtrate is washed with water. Afterdrying and evaporation, 21.5 g of3,3-ethylenedioxy-1-methyl-5α-androstan-17-one is obtained as the crudeproduct.

It has now been found that the 17α-alkyl steroids of formula I derivedfrom mesterolone show antiandrogenic properties upon topicaladministration. These 17α-alkyl steroids counteract androgens which arepresent or administered. Thus, using the compounds of formula I, thegrowth of the flank organs and the sebaceous glands of the ears,stimulated by testosterone propionate, is inhibited in castrated malehamsters. On the other hand, other androgen-dependent organs, such asprostate and seminal vesicles are not significantly affected.

The topical antiandrogenic effect was determined as follows.

Male fertile hamsters weighing about 80 grams are castrated and 0.1 mgof testosterone propionate is subcutaneously administered daily as asubstitute. The right ear and the right flank organ are treated twicedaily with 0.01 ml of a 3% solution of the antiandrogen to be tested inan organic solvent, preferably acetone, over a period of 3 weeks. On the22nd day, the animals are killed with ether; the prostate, seminalvesicles and lumbar organs are prepared and weighed, the ears areprocessed histologically, and the areas of the sebaceous glands aremeasured. Using the ears of other treated animals, the incorporation of¹⁴ C-labeled glucose into the lipids of the sebaceous glands ismeasured.

It has been found that the sebaceous gland conglomerates, as the size ofthe flank organs and the sebaceous glands at the ventral sides of theear lobes of the hamster, which latter glands can be well distinguishedand readily detected planimetrically, are dependent on androgen. As aparameter for the sebaceous gland function, the incorporation of ¹⁴C-labeled precursors in lipid synthesis is measured.

By comparing the areas of the sebaceous glands, the weights of the flankorgans, and the lipogenesis of the side respectively treated with theantiandrogen, along with solvent control, a measure is obtained for thelocal effect of the antiandrogen.

For topical application, to mammals, e.g., humans, the 17α-alkylsteroids of this invention can be processed with conventional excipientsinto solutions, suspensions, gels, ointments, creams, powders or otherpreparations. Suitable excipients include, for example, water, ethanol,propanol, glycerin, methylcellulose, hydroxypropylcellulose,carboxypolymethylene, etc. The antiandrogen is preferably used in aconcentration of 0.05-5.0% by weight, based on the total weight of thepreparation. The preparations can be utilized for the topical treatmentof diseases such as acne, seborrhea, alopecia and hirsutism analogouslyto the use of the known topical agent Topterone (U.S. Pat. No.4,039,669) e.g., by administration 1-3 times a day to the affected area.

In an experiment, the right flank organ and the right ear of castratedSyrian golden hamsters were topically treated for 21 days twice dailywith 0.01 ml of a 3% ethanolic solution of17β-hydroxy-1α-methyl-17α-n-propyl-5α-androstan-3-one (A). The goldenhamsters were furthermore treated daily with 0.1 mg of testosteronepropionate in benzyl benzoate/castor oil in a ratio of 1:100 viasubcutaneous administration. On the 22nd day, the animals weresacrificed; seminal vesicles, prostates, and flank organs were preparedand weighed, and the area sizes of the sebaceous glands of thehistologically further processed ears were measured. Ten animals wereused per experiment.

The results are shown in the following table:

    __________________________________________________________________________    Seminal Vesicles                                                                            Prostate                                                                             Flank Organs mg                                                                           Areas mm.sup.2                               mg            mg     Right Left  Right                                                                              Left                                    __________________________________________________________________________    A    1101 ± 34.58                                                                        355 ± 21.91                                                                       35 ± 1.92                                                                        67 ± 3.64                                                                        0.0634 ±                                                                        0.1516 ±                                                              0.0054                                                                             0.021                                   Control                                                                            1106 ± 46.52                                                                        404 ± 23.82                                                                       70 ± 3.53                                                                        72 ± 3.67                                                                        0.2309 ±                                                                        0.2428 ±                                                              0.026                                                                              0.023                                   __________________________________________________________________________     A marked reduction in weight of the treated righthand flank organ and a       reduction of the sebaceous gland size (area) of the treated right ear are     determined. With local application of A, the seminal vesicle weight is        affected hardly at all, and the prostate weight is only slightly              influenced.                                                              

In another experiment, the sebum production of the sebaceous glands ofhamster ears treated as above was measured by incorporation of (¹⁴ C)sodium acetate into the lipids of the sebaceous gland cells in vitro andsubsequent determination of radioactivity in the lipid extract. Theaverage values and the standard deviations were calculated from theradioactivity of the individual specimens. The percentage inhibition oflipogenesis of the treated right ears was calculated as compared withthe control group, i.e. the right ears treated with the solvent. Thisexperiment revealed a marked and dose-dependent reduction of lipogenesisin the treated ears.

    ______________________________________                                        A         Reduction of Lipogenesis                                            (%)       (%)                                                                 ______________________________________                                        3         43.8 ± 7.0                                                       1         51.9 ± 7.6                                                       0.3       26.25 ± 21.0                                                     0.1       33.6 ± 14.0                                                      ______________________________________                                    

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the disclosure in any way whatsoever. In the followingexamples, all temperatures are set forth uncorrected in degrees Celsius;unless otherwise indicated, all parts and percentages are by weight.

EXAMPLE 1

800 mg of magnesium filings are reacted in 20 ml of absolute ether with2 ml of allyl bromide in 5 ml of absolute ether to obtain allylmagnesiumbromide. At room temperature 2 g of3,3-ethylenedioxy-1α-methyl-5α-androstan-17-one in 5 ml ofdichloromethane is added to this solution, and the latter is agitatedfor 3 hours. The ice-cooled reaction solution is then gradually combinedwith saturated ammonium chloride solution, diluted with ether, washedwith saturated ammonium chloride solution and water, yielding, afterdrying and evaporation, 2.1 g of3,3-ethylenedioxy-1α-methyl-17α-(2-propenyl)-5α-androstan-17β- ol as acrude product.

2.1 g of3,3-ethylenedioxy-1α-methyl-17α-(2-propenyl)-5α-androstan-17β-ol ishydrogenated in 105 ml of methanol with 210 mg of palladium on charcoal(10%) until one equivalent of hydrogen has been absorbed. The catalystis filtered off and the filtrate evaporated under vacuum, yielding 2.1 gof 3,3-ethylenedioxy-1α-methyl-17α-n-propyl-5α-androstan-17β-ol as acrude product. A sample recrystallized from diisopropyl ether melts at150°-150.5° C.

1.5 g of 3,3-ethylenedioxy-1α-methyl-17α-n-propyl-5α-androstan-17β-ol isstirred at room temperature in 30 ml of methanol and 3 ml of water with1.5 g of oxalic acid for 2 hours. The mixture is then diluted withether, washed with water, and dried. After evaporation the residue ischromatographed on silica gel, producing 1.1 g of17β-hydroxy-1α-methyl-17α-n-propyl-5α-androstan-3-one as an oil.

[α]_(D) ²³ =+7.5° (chloroform).

EXAMPLE 2

1.25 g of 3,3-ethylenedioxy-1α-methyl-5α-androstan-17-one is combined in12.5 ml of absolute tetrahydrofuran, under ice cooling and passing argonover the mixture, with 3.5 ml of a butyllithium solution (15% in hexane)and stirred for 22 hours at room temperature. The excess reagent is thendecomposed with water, the reaction solution is diluted with ether andwashed with water. After drying and evaporation the residue ischromatographed on silica gel, thus obtaining 950 mg of17α-n-butyl-3,3-ethylenedioxy-1α-methyl-5α-androstan-17.beta.-ol as acrude product.

950 mg of17α-n-butyl-3,3-ethylenedioxy-1α-methyl-5α-androstan-17.beta.-ol isstirred in 10 ml of methanol with 1 ml of 8 vol-% sulfuric acid for 30minutes at room temperature. The mixture is diluted with ether, washedwith water, and dried. The residue obtained after evaporation ischromatographed on silica gel, thus producing 620 mg of17α-n-butyl-17β-hydroxy-1α-methyl-5α-androstan-3-one as an oil.

[α]_(D) ²³ =+5.6° (chloroform).

EXAMPLE 3

Under pressure, 400 mg of lithium is introduced into 20 ml of ice-cooledabsolute tetrahydrofuran, and then 7.8 ml of 1-bromopentane is addeddropwise. After the reaction is finished, 1.6 g of3,3-ethylenedioxy-1α-methyl-5α-androstan-17-one, dissolved in 8 ml ofabsolute tetrahydrofuran, is added thereto. The mixture is agitated for48 hours at room temperature under argon and then worked up as describedin Example 2. Chromatography on silica gel yields 1.1 g of3,3-ethylenedioxy-1α-methyl-17α-n-pentyl-5α-androstan-17β-ol as an oil.

1.0 g of 3,3-ethylenedioxy-1α-methyl-17α-n-pentyl-5α-androstan-17β-ol isused for ketal splitting as in Example 2 and then worked up. Afterchromatography on silica gel, 720 mg of17β-hydroxy-1α-methyl-17α-n-pentyl-5α-androstan-3-one is obtained as anoil.

[α]_(D) ²³ =+4° (chloroform).

EXAMPLE 4

500 mg of lithium is introduced under pressure into 30 ml of ice-cooled,absolute tetrahydrofuran and then 11.3 ml of 1-bromohexane is addeddropwise. After the reaction is finished, 2.0 g of3,3-ethylenedioxy-1α-methyl-5α-androstan-17-one in 10 ml of absolutetetrahydrofuran is added dropwise to the mixture, and the latter isstirred under argon for 48 hours at room temperature. The mixture isworked up as described in Example 2 and chromatographed on silica gel,yielding 950 mg of3,3-ethylenedioxy-17α-n-hexyl-1α-methyl-5α-androstan-17.beta.-ol as anoil.

850 mg of3,3-ethylenedioxy-17α-n-hexyl-1α-methyl-5α-androstan-17.beta.-ol isreacted under ketal-splitting conditions as in Example 2 and then workedup. After chromatography on silica gel, 630 mg of17α-n-hexyl-17β-hydroxy-1α-methyl-5α-androstan-3-one is obtained as anoil.

[α]_(D) ²³ =+4° (chloroform).

EXAMPLE 5

1.5 g of magnesium filings is reacted in 40 ml of absolutetetrahydrofuran with 4.9 ml of ethyl bromide to obtain ethylmagnesiumbromide. This solution is added dropwise under ice cooling to 40 ml ofabsolute tetrahydrofuran, through which acetylene is conducted. 3 g of3,3-ethylenedioxy-1α-methyl-5α-androstan-17-one is added to theacetylenemagnesium bromide solution, and the mixture is stirred for 23hours at room temperature. Under ice cooling the excess reagent is thendecomposed with saturated ammonium chloride solution, then diluted withether, and washed with water. After drying and evaporation the residueis chromatographed on silica gel, thus obtaining 2.65 g of17α-ethynyl-3,3-ethylenedioxy-1α-methyl-5α-androstan-17.beta.-ol as acrude product.

1.4 g of17α-ethynyl-3,3-ethylenedioxy-1α-methyl-5α-androstan-17.beta.-ol ishydrogenated in 70 ml of methanol with 200 mg of palladium on charcoal(5%) until 2 equivalents of hydrogen has been absorbed. The mixture isthen filtered off from the catalyst and evaporated under vacuum,yielding 1.4 g of17α-ethyl-3,3-ethylenedioxy-1α-methyl-5α-androstan-17.beta.-ol as anoil.

1.4 g of 17α-ethyl-3,3-ethylenedioxy-1α-methyl-5α-androstan-17.beta.-olis used for ketal splitting as described in Example 2 and worked up.After chromatography on silica gel and recrystallization fromdiisopropyl ether, 1.1 g of17α-ethyl-17β-hydroxy-1α-methyl-5α-androstan-3-one is obtained, m.p.151.5°-152.5° C.

EXAMPLE 6

5.0 g of 17β-hydroxy-1α-methyl-17α-n-propyl-5α-androstan-3-one isstirred in 5 ml of absolute tetrahydrofuran with 5.0 g of lithiumtri-tert.-butoxyaluminum hydride for 3 hours at room temperature. Themixture is diluted with ether, washed with dilute sulfuric acid andwater, dried, and evaporated. After chromatography on silica gel andrespective recrystallization from diisopropyl ether, 860 mg of1α-methyl-17α-n-propyl-5α-androstane-3β,17β-diol, m.p. 117°-118° C., and3.3 g of 3α-isomer, m.p. 143°-144° C., are obtained.

EXAMPLE 7

1.5 g of 17β-hydroxy-1α-methyl-17α-n-propyl-5α-androstan-3-one isallowed to stand at room temperature in 6 ml of pyridine with 3 ml ofacetic anhydride for 16 hours, after the addition of 75 mg of4-dimethylaminopyridine. After the mixture has been precipitated intoice water and recrystallized from hexane, 1.3 g of17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3-one is obtained, m.p.128°-129° C.

EXAMPLE 8

1.0 g of 17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3-one isreacted as described in Example 6 with lithium tri-tert.-butoxyaluminumhydride and worked up. After chromatography on silica gel, 650 mg of17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3.beta.-ol is obtainedas an oil.

EXAMPLE 9

250 mg of 17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3.beta.-ol isallowed to stand at room temperature for 48 hours in 1 ml of pyridinewith 0.5 ml of butyric anhydride. The mixture is diluted with ether,washed repeatedly with water, dried, and evaporated. The residue ischromatographed on silica gel, yielding 270 mg of17β-acetoxy-3β-butyryloxy-1α-methyl-17α-n-propyl-5.alpha.-androstane asan oil.

EXAMPLE 10

400 mg of 17β-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3.beta.-ol iscombined in 2.8 ml of absolute dichloromethane and 1.8 ml offormaldehyde dimethylacetal with a mixture of 600 mg of kieselguhr W 20and 300 mg of phosphorus pentoxide and stirred for 45 minutes at roomtemperature. The mixture is vacuum-filtered from the insolublecomponents and washed with dichloromethane containing 3-5%triethylamine. The crude product obtained after evaporation ischromatographed on silica gel, thus producing 280 mg of17β-acetoxy-3β-methoxymethoxy-1α-methyl-17α-n-propyl-5α-androstane.

EXAMPLE 11

400 mg of 17β-hydroxy-1α-methyl-17α-n-propyl-5α-androstan-3-one isstirred for 42 hours at room temperature in 1.6 ml of pyridine and 0.8ml of enanthic anhydride with the addition of 40 mg of4-dimethylaminopyridine. The mixture is diluted with ether, washed withwater, dried, and evaporated. The residue is chromatographed on silicagel, yielding 370 mg of17β-heptanoyloxy-1α-methyl-17α-n-propyl-5α-androstan-3-one as an oil.

EXAMPLE 12

7.0 g of 3,3-ethylenedioxy-1α-methyl-5α-androstan-17-one is combined in70 ml of tetrahydrofuran with 2.8 g of magnesium filings; 14.35 ml ofcrotyl bromide in 15 ml of tetrahydrofuran is then gradually addeddropwise to the reaction mixture and the latter is stirred for 45minutes at room temperature. The excess reagent is decomposed under icecooling with ammonium chloride solution; then the reaction solution isdiluted with ether, washed with water, dried, and evaporated. Theresidue is chromatographed on silica gel, thus obtaining 1.95 g of3,3-ethylenedioxy-1α-methyl-17α-(1-methyl-2-propenyl)-5α-androstan-17β-olas a crude product.

1.92 g of3,3-ethylenedioxy-1α-methyl-17α-(1-methyl-2-propenyl)-5α-androstan-17α-olis stirred in 19.2 ml of methanol with 1.92 ml of 8 vol-% sulfuric acidfor 15 minutes at room temperature. The mixture is then diluted withether, washed neutral with water, dried, and evaporated. The residue ischromatographed on silica gel. Recrystallization from diisopropyl etheryields 780 mg of17β-hydroxy-1α-methyl-17α-(1-methyl-2-propenyl)-5α-androstan-3-one, m.p.148.5°-150° C.

770 mg of 17β-hydroxy-1α-methyl-17α-(1-methyl-2-propenyl)-5α-androstan-3-one is hydrogenated in 5 ml of tetrahydrofuran and 15 ml of methanolwith 150 mg of palladium on charcoal (10%) until one equivalent ofhydrogen has been absorbed. The catalyst is filtered off and thefiltrate evaporated under vacuum. The residue is chromatographed onsilica gel. Recrystallization from diisopropyl ether yields 440 mg of17β-hydroxy-1α-methyl-17α-(1-methyl-n-propenyl)-5α-androstan-3-one, m.p.172.5°-173.5° C.

EXAMPLE 13

700 mg of 1α-methyl-17α-n-propyl-5α-androstane-3α,17β-diol (preparedaccording to Example 6, m.p. 143°-144° C.) is allowed to stand at roomtemperature for 22 hours in 2.8 ml of pyridine and 1.4 ml of aceticanhydride. After ice water precipitation, the thus-obtained crudeproduct is chromatographed on silica gel, yielding 760 mg of3α-acetoxy-1α-methyl-17α-n-propyl-5α-androstan-17.beta.-ol as an oil.

EXAMPLE 14

1.5 g of 1α-methyl-17α-n-propyl-5α-androstane-3α,17β-diol is allowed tostand in 6 ml of triethylamine and 1.5 ml of acetic anhydride with 50 mgof 4-dimethylaminopyridine for 6 days at room temperature. After icewater precipitation, the thus-produced crude compound is chromatographedon silica gel, yielding 1.08 g of3α,17β-diacetoxy-1α-methyl-17α-n-propyl-5α-androstane, m.p. 96°-99° C.

EXAMPLE 15

One gram of3,3-ethylenedioxy-1α-methyl-17α-(2-propenyl)-5α-androstan-17β-ol(prepared according to Example 1) is stirred in 10 ml of methanol with 1ml of 8 vol-% sulfuric acid for 15 minutes at room temperature and thenworked up analogously to Example 12. Recrystallization from diisopropylether yields 710 mg of17β-hydroxy-1α-methyl-17α-(2-propenyl)-5α-androstan-3-one, m.p.115°-116° C.

The preceding examples can be repeated with similar success bysubstituting the generically and specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

What is claimed is:
 1. A 17α-substituted steroid of the formula ##STR4##wherein R₁ is hydrogen, an acyl group of a C₁₋₁₇ hydrocarbon carboxylicor sulfonic acid, C₁₋₅ alkyl, C₁₋₅ -alkenyl, C₁₋₅ -alkyl or C₁₋₅-alkenyl interrupted by an oxa atom, cyclopentyl or tetrahydropyranyl,R₂is C₃₋₄ -alkyl, and X is oxygen or H(OR₃) wherein R₃ is hydrogen, anacyl group of a C₁₋₁₇ hydrocarbon carboxylic or sulfonic acid, C₁₋₅alkyl, C₁₋₅ -alkenyl, cyclopentyl or tetrahydropyranyl. 2.17β-Hydroxy-1α-methyl-17α-n-propyl-5α-androstan-3-one, a compound ofclaim
 1. 3. 17α-n-Butyl-17β-hydroxy-1α-methyl-5α-androstan-3-one, acompound of claim
 1. 4.1α-Methyl-17α-n-propyl-5α-androstane-3β,17β-diol, a compound of claim 1.5. 17β-Acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3-one, a compound ofclaim
 1. 6. 17β-Acetoxy-1α-methyl-17α-n-propyl-5α-androstan-3β-ol, acompound of claim
 1. 7.17β-Acetoxy-3β-butyryloxy-1α-methyl-17α-n-propyl-5α-androstane, acompound of claim
 1. 8.17β-Heptanoyloxy-1α-methyl-17α-n-propyl-5.alpha.-androstan-3-one, acompound of claim
 1. 9.1α-Methyl-17α-n-propyl-5α-androstane-3α,17β-diol, a compound of claim 1.10. 3α,17β-Diacetoxy-1α-methyl-17α-n-propyl-5α-androstane, a compound ofclaim
 1. 11. A compound of claim 1 wherein R₁ is C₁₋₅ alkyl, C₁₋₅alkenyl, C₁₋₅ -alkyl or C₁₋₅ -alkenyl interrupted by an oxa atom,cyclopentyl or tetrahydropyranyl.
 12. A compound of claim 1 wherein R₁is an acyl group of a C₁₋₁₇ optionally substituted, hydrocarboncarboxylic or sulfonic acid.
 13. A compound of claim 12 wherein R₁ ischloroacetyl, glycoloyl, trifluoroacetyl, succinyl, glutaryl, adipoyl,benzoyl, dimethylaminopropionyl, nicotinoyl or isonicotinoyl.
 14. Acompound of claim 13 wherein X is OR₃ wherein R₃ is an acyl group of aC₁₋₁₇ hydrocarbon carboxylic or sulfonic acid, C₁₋₅ alkyl, C₁₋₅-alkenyl, cyclopentyl or tetrahydropyranyl.
 15. A compound of claim 1wherein R₁ is H.
 16. A compound of claim 15 wherein X is OR₃ wherein R₃is an acyl group of a C₁₋₁₇ hydrocarbon carboxylic or sulfonic acid,C₁₋₅ alkyl, C₁₋₅ -alkenyl, cyclopentyl or tetrahydropyranyl.
 17. Acompound according to claim 1 wherein X is H(OR₃) and R₃ is cyclopentylor tetrahydropyranyl.
 18. A compound according to claim 1 wherein R₁ isC₁₋₅ -alkyl or C₁₋₅ -alkenyl interrupted by an oxa-atom.
 19. A compoundaccording to claim 1 wherein R₁ is C₁₋₅ -alkyl or C₁₋₅ -alkenylinterrupted by an oxa-atom, cyclopentyl or tetrahydropyranyl.
 20. Acompound according to claim 1 wherein X is oxygen.
 21. A pharmaceuticalcomposition comprising an antiandrogenically topically effective amountof a compound of the formula ##STR5## wherein R₁ is hydrogen, an acylgroup of a C₁₋₁₇ hydrocarbon carboxylic or sulfonic acid, C₁₋₅ alkyl,C₁₋₅ -alkenyl, C₁₋₅ -alkyl or C₁₋₅ -alkenyl interrupted by an oxa atom,cyclopentyl or tetrahydropyranyl,R₂ is C₃₋₄ -alkyl, and X is oxygen orH(OR₃) wherein R₃ is hydrogen, an acyl group of a C₁₋₁₇ hydrocarboncarboxylic or sulfonic acid, C₁₋₅ -alkyl, C₁₋₅ -alkenyl, cyclopentyl ortetrahydropyranyl, and a pharmaceutically acceptable carrier for topicalformulations.
 22. A pharmaceutical composition comprising anantiandrogenically topically effective amount of a compound of theformula ##STR6## wherein R₁ is hydrogen, an acyl group of a C₁₋₁₇hydrocarbon carboxylic or sulfonic acid, C₁₋₅ alkyl, C₁₋₅ -alkenyl, C₁₋₅-alkyl or C₁₋₅ -alkenyl interrupted by an oxa atom, cyclopentyl ortetrahydropyranyl,R₂ is C₃₋₄ -alkyl, and X is oxygen and apharmaceutically acceptable carrier for topical formulations.